Disuse osteoporosis is caused by physical inactivity. It increases fracture risk for patients who have had a stroke or spinal cord injury. Animals also lose bone mass and strength during physical inactivity because bone formation is uncoupled from resorption. In humans, bone loss during disuse is associated with increased calcium excretion. In contrast, bears do not eat, drink, urinate, or defecate (i.e., excrete calcium) during hibernation, and blood calcium concentration remains constant throughout the year. In this research proposal, it is hypothesized that hibernating bears maintain trabecular bone mineral, architecture, and strength during annual periods of physical inactivity because they reduce bone resorption and maintain balanced bone resorption and formation. If this is true, it will support the idea that bears have biological mechanisms to prevent disuse osteoporosis. This grant proposes to measure histological indices of trabecular bone formation and resorption, bone mineral and architectural parameters, and gene expression related to bone resorption before, during, and after hibernation. Bone samples will be collected from hunter-killed bears and from a bear research facility. Microscopically, the degree of bone resorption and formation activity will be quantified with image analysis software. The bone samples will be mechanically tested to determine their fracture strength. The level of mineralization in the bones and the micro-architecture will be quantified with micro-computed tomography. If the bones are not weaker during and after hibernation than before hibernation, it will support the theory the bears have evolved biological mechanisms to prevent disuse osteoporosis. By quantifying the level of gene expression related to bone resorption, we will begin to quantify this biological mechanism. Future research will be aimed at translating the biological mechanism to a clinical treatment for human osteoporosis. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to quantify the physiological changes that occur in bone remodeling in hibernating bears. Elucidating the biological mechanisms that prevent bone loss during prolonged physical inactivity during hibernation may help us design therapies to treat human osteoporosis. This may be accomplished by targeting genes and circulating hormones which are differentially expressed in bears and humans during physical inactivity.